The MTR4 helicase recruits nuclear adaptors of the human RNA exosome using distinct arch-interacting motifs

Lingaraju, Mahesh; Johnsen, Dennis; Schlundt, Andreas; Langer, L.M.; Basquin, J.; Sattler, Michael; Jensen, Torben Heick; Falk, Sebastian; Conti, Elena

doi:10.1038/s41467-019-11339-x

Cited by 45 publications

(53 citation statements)

References 59 publications

(91 reference statements)

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“…ZFC3H1 and ZC3H3 form Poly(A) Tail eXosome Targeting (PAXT) complex with MTR4, poly(A) binding protein PABN1 and RNA binding proteins RMB26/27 (53,82,84,85). In addition to the Zinc-finger domain, ZCCHC8 also contains a hydrophobic region called "arch interacting motif" (AIM) that mediates interaction with MTR4 arch domain and the C-terminal region that stimulates helicase activity of MTR4 (86,87). AIM region is also present in other exosome co-factors-ZCCHC7 (Air2), rRNA processing factors NOP53 and NVL (88,89).…”

Section: Mub1 Regulates Exosome Degradation Of the Stress-induced Mrnasmentioning

confidence: 99%

RNA-binding protein Mub1 and the nuclear RNA exosome act to fine-tune environmental stress response

Birot

Kilchert

Kuś

et al. 2020

Preprint

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ABSTRACTThe nuclear RNA exosome plays a key role in quality control and processing of multiple protein-coding and non-coding transcripts made by RNA polymerase II. A mechanistic understanding of exosome function remains a challenge given it has multiple roles in RNA regulation. Here we have analysed changes in the poly(A)+ RNA transcriptome and interactome provoked by mutations in three distinct subunits of the nuclear RNA exosome. We have identified multiple proteins whose occupancy on RNA is altered in the exosome mutants. We demonstrate that the Zinc-finger protein Mub1 regulates exosome dependent transcripts that encode stress-responsive proteins. Furthermore, we assess impact of the exosome inactivation upon RNA binding of the components of the mRNA processing machineries such as spliceosome and mRNA cleavage polyadenylation complex. We show that mutations in the exosome lead to accumulation of the components of U1 and U2 snRNPs on poly(A)+ RNA and depletion of the components of the activated spliceosome from RNA suggesting that the early stages of spliceosome assembly might provide a critical quality control step. Collectively, our data provide a global view of how RNA metabolism is affected in the exosome-deficient cells and reveal RNA-binding proteins that may act as novel exosome cofactors.

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Section: Mub1 Regulates Exosome Degradation Of the Stress-induced Mrnasmentioning

confidence: 99%

RNA-binding protein Mub1 and the nuclear RNA exosome act to fine-tune environmental stress response

Birot

Kilchert

Kuś

et al. 2020

Preprint

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“…Recent work has identified a new Mtr4 binding motif within the NTD of NVL2 from higher eukaryotic organisms. This motif is reminiscent of the motif found in Utp18 and Nop53 [114]. Analogous to Nop53 and Utp18, this short motif in NVL2 binds to the Arch domain of Mtr4 and competes for the same binding site [114].…”

Section: From the Nucleolus To The Cytoplasm: Mechanistic Insightsmentioning

confidence: 99%

“…This motif is reminiscent of the motif found in Utp18 and Nop53 [114]. Analogous to Nop53 and Utp18, this short motif in NVL2 binds to the Arch domain of Mtr4 and competes for the same binding site [114]. Thus, vertebrate homologues of NVL2 are nuclear adapters for the Mtr4-associated exosome.…”

Section: From the Nucleolus To The Cytoplasm: Mechanistic Insightsmentioning

confidence: 99%

Shaping the Nascent Ribosome: AAA-ATPases in Eukaryotic Ribosome Biogenesis

Prattes

Bergler

et al. 2019

Biomolecules

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AAA-ATPases are molecular engines evolutionarily optimized for the remodeling of proteins and macromolecular assemblies. Three AAA-ATPases are currently known to be involved in the remodeling of the eukaryotic ribosome, a megadalton range ribonucleoprotein complex responsible for the translation of mRNAs into proteins. The correct assembly of the ribosome is performed by a plethora of additional and transiently acting pre-ribosome maturation factors that act in a timely and spatially orchestrated manner. Minimal disorder of the assembly cascade prohibits the formation of functional ribosomes and results in defects in proliferation and growth. Rix7, Rea1, and Drg1, which are well conserved across eukaryotes, are involved in different maturation steps of pre-60S ribosomal particles. These AAA-ATPases provide energy for the efficient removal of specific assembly factors from pre-60S particles after they have fulfilled their function in the maturation cascade. Recent structural and functional insights have provided the first glimpse into the molecular mechanism of target recognition and remodeling by Rix7, Rea1, and Drg1. Here we summarize current knowledge on the AAA-ATPases involved in eukaryotic ribosome biogenesis. We highlight the latest insights into their mechanism of mechano-chemical complex remodeling driven by advanced cryo-EM structures and the use of highly specific AAA inhibitors.

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“…The arch domain faces the entrance of the helicase channel at the top of the DExH core and contains a KOW domain capable of binding both singlestranded and structured RNAs (Jackson et al 2010;Weir et al 2010). In addition to RNA binding, both domains of Mtr4 serve as protein binding platforms: the DExH core, for example, binds the amino-terminal region of Mpp6 (Gerlach et al 2018;Schuller et al 2018 ;Weick et al 2018), and the KOW domain binds so-called arch-interacting motifs (AIMs) of adaptor proteins, such as in the ribosomal biogenesis factor Nop53 (Thoms et al 2015;Falk et al 2017b;Lingaraju et al 2019). The essential unwinding activity of Mtr4 likely serves to prepare substrates for threading into the narrow entry pore of the exosome core, which is only wide enough to accommodate single-stranded RNA substrates (Makino et al 2013a).…”

Section: Architecture Of the Rna Exosome: The Nuclear Cofactorsmentioning

confidence: 99%

To Process or to Decay: A Mechanistic View of the Nuclear RNA Exosome

Lingaraju

Schuller

Falk

et al. 2019

Cold Spring Harb Symp Quant Biol

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The RNA exosome was originally discovered in yeast as an RNA-processing complex required for the maturation of 5.8S ribosomal RNA (rRNA), one of the constituents of the large ribosomal subunit. The exosome is now known in eukaryotes as the major 3′-5′ RNA degradation machine involved in numerous processing, turnover, and surveillance pathways, both in the nucleus and the cytoplasm. Yet its role in maturing the 5.8S rRNA in the pre-60S ribosomal particle remains probably the most intricate and emblematic among its functions, as it involves all the RNA unwinding, degradation, and trimming activities embedded in this macromolecular complex. Here, we propose a comprehensive mechanistic model, based on current biochemical and structural data, explaining the dual functions of the nuclear exosome-the constructive versus the destructive mode. ARCHITECTURE OF THE RNA EXOSOME: THE CORE COMPLEX The RNA exosome is an ancient machine with prokaryotic ancestry that has been likened to a proteasome for RNA (for reviews, see van Hoof and Parker 1999; Lorentzen and Conti 2006; Makino et al. 2013b). In eukaryotes, the core complex is formed by 10 different subunits (Exo10) (Fig. 2). Studies in yeast and human revealed that

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The MTR4 helicase recruits nuclear adaptors of the human RNA exosome using distinct arch-interacting motifs

Cited by 45 publications

References 59 publications

RNA-binding protein Mub1 and the nuclear RNA exosome act to fine-tune environmental stress response

RNA-binding protein Mub1 and the nuclear RNA exosome act to fine-tune environmental stress response

Shaping the Nascent Ribosome: AAA-ATPases in Eukaryotic Ribosome Biogenesis

To Process or to Decay: A Mechanistic View of the Nuclear RNA Exosome

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